期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 338, 期 3, 页码 1013-1022出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.111.179200
关键词
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资金
- World Class University [R31-2008-00-10056-0]
- Ministry of Education, Science, and Technology, Republic of Korea [2010-0029233]
Targeting tumor necrosis factor (TNF)-alpha-mediated signal pathways may be a promising strategy for developing chemopreventive agents, because TNF-alpha-mediated cyclooxygenase (COX)-2 expression plays a key role in inflammation and carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] exerts anticarcinogenic effects, although little is known about the underlying molecular mechanisms and specific targets of this compound. In the present study, we found that luteolin inhibited TNF-alpha-induced COX-2 expression by down-regulating the transactivation of nuclear factor-kappa B and activator protein-1. Furthermore, luteolin inhibited TNF-alpha-induced phosphorylation of mitogen-activated protein kinase/extra-cellular signal-regulated kinase (ERK) kinase 1/ERK/p90(RSK), mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase/c-Jun, and Akt/p70(S6K). However, it had no effect on the phosphorylation of p38. These effects of luteolin on TNF-alpha-mediated signaling pathways and COX-2 expression are similar to those achieved by blocking tumor progression locus 2 serine/threonine kinase (TPL2) using pharmacologic inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro and in TPL2 immunoprecipitation kinase assays by binding directly in an ATP-competitive manner. Overall, these results indicate that luteolin exerts potent chemopreventive activities, which primarily target TPL2.
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